Biomedical subjects
Publications and source records attributed to H H Saneii.
Omission libraries, synthesized by omitting one amino acid in all coupling positions, are very efficient tools for the rapid identification of the amino acid components of bioactive peptides. Based on the determined amino acids, an occurrence library can be defined and prepared which is much less complex than the full one while still comprising the bioactive peptide.
The synthesis and in vitro renin inhibitory potencies of angiotensinogen (ANG) analogues having amide (CONH) bond replacements at P1-P1', the Leu-Val cleavage site, corresponding to Leu psi[CH2SO]Val, and the trans olefinic analogue of statine (Sta), 4(S)-amino-6-methyl-2(E)-heptenoic acid (dehydrostatine, Dhs), are reported. These are compared to P1-P1' Leu psi[CH2NH]Val-, Sta-, or Phe-Phe-substituted analogues of the same template. The Dhs pseudodipeptide was found to be an adequate mimic of a trans CONH bond and gave a peptide, H-Pro-His-Pro-Phe-His-Dhs-Ile-His-D-Lys-OH, approximately equal in potency to a Phe-Phe-containing inhibitor, but 200-fold less potent than its Sta-substituted congener. That the enhanced potency of the Sta-containing peptide most likely depends on hydrogen bonding as well as tetrahedral geometry is indicated by the 50-100-fold lower potency of the tetrahedral Leu psi[CH2S]Val and Leu psi[CH2SO]Val analogues as compared to the Leu psi[CH2NH]Val-containing congener.
Atrial natriuretic peptides lower arterial pressure, cardiac filling pressure, and cardiac output. In isolated, Langendorff-perfused guinea pig hearts, atriopeptin II, the 23-amino acid atrial natriuretic peptide, is also a potent coronary vasoconstrictor. The median effective dose for atriopeptin II in guinea pig hearts is 26 nanomoles, the threshold constrictor dose is 5 nanomoles, and flow nearly ceases at a dose of 100 nanomoles in perfused hearts at constant pressure. Similar concentrations of atriopeptin II also cause coronary vasoconstriction in rat and dog heart preparations. The disulfide bridge is necessary for vasoconstrictor activity; reduction of this bridge abolishes the activity, as it does the other biological activities of atrial natriuretic peptides.
Addition of synthesized atriopeptin II (AP-2), a 23 amino acid peptide of rat atria, to rat thoracic aorta smooth muscle cells results in the stimulation of cyclic GMP production by the cells. The EC50 for the effect is 81 nM and a 7 fold increase occurs at 10 microM AP-2. Cyclic GMP levels increased within 15 seconds after the addition of AP-2 and were maximal at 5 minutes. Cyclic GMP levels in primary rabbit kidney cells were increased 15 fold by 10 microM AP-2. However, no increase in cyclic GMP was detected in WI-38 fibroblast cells after the addition of 10 microM AP-2. Cyclic AMP levels were not affected by AP-2 in any of these cell systems. The effect upon cyclic GMP accumulation was specific for AP-2; none of the other compounds or peptides tested affected cyclic GMP levels.
Atrial natriuretic peptides cause natriuresis, kaliuresis, diuresis, and hypotension. They relax vascular smooth muscle in vitro, and they dilate renal vessels in vivo. Hence, we tested the hypothesis that they produce hypotension by lowering total peripheral resistance. The studies were performed in conscious chronically instrumented sheep standing quietly in their cages. Atriopeptin II (AP II) was infused into the right atrium for 30 min at 0.1 nmol X kg-1 X min-1. Atriopeptin II lowers arterial pressure (9%, P less than 0.05) by lowering cardiac output (18%, P less than 0.05), stroke volume (28%, P less than 0.05), and right atrial pressure (2.3 mmHg, P less than 0.05). Heart rate and total peripheral resistance increase (16 and 13%, respectively, P less than 0.05). Partial ganglionic blockade with trimethaphan camsylate during AP II infusion prevents the increases in heart rate and total peripheral resistance. The changes in right atrial pressure, stroke volume, and cardiac output persist, and arterial pressure falls further (27%, P less than 0.05). These hemodynamic data are consistent with direct AP II-induced relaxation of venous smooth muscle with reduction of venous return, right atrial pressure, stroke volume, cardiac output, and arterial pressure, followed by reflex activation of the sympathetic nervous system to increase heart rate and total peripheral resistance. Because partial ganglionic blockade alone and AP II alone cause similar reductions in right atrial pressure (2.1 and 2.3 mmHg, respectively) but AP II causes a greater fall in stroke volume (28 vs. 13%), it is possible that AP II also causes coronary vasoconstriction.
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